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PubMed1992

Isolated hyperthermic liver perfusion with cytostatic-containing perfusate activates the complement cascade.

Eight patients with advanced liver malignancy undergoing isolated hyperthermic liver perfusion with melphalan and cisplatin were studied with regard to complement activation and formation of anaphylatoxins (C3a and C5a) and terminal C5b-9 complement complexes (TCCs). Blood samples for complement variables (C1-INH, C3, C4, C5, C3a, C5a and TCCs) were taken before surgery, 1 min before the start of perfusion, 1, 2 and 3 h after the start of perfusion, and 24 h after operation. Samples were drawn from the perfusate 1 h after the start of perfusion. Activation of complement was observed during perfusion. Raised plasma concentrations of C3a and TCCs were recorded and high levels of C3a and TCCs were found in the perfusate. In vitro tests indicated that melphalan and cisplatin may activate complement. This activation occurred at 37 and 42 degrees C but was more pronounced at 42 degrees C.

Adult↗
PubMed1986

Biocompatibility of different hemodialysis membranes: activation of complement and leukopenia.

The ability of three hollow-fiber dialyzers (Cuprophane [CU], polymethylmethacrylate [PMMA], and polyacrylonitrile [PAN]) to activate complement and to induce leukopenia was studied prospectively in six patients on long-term hemodialysis. CU membranes caused the most intense complement activation with C3a, C3d, and C5a levels peaking 15 min after beginning dialysis. Total white blood cell (WBC) counts dropped simultaneously by 76%, and the decrease in leukocytes was inversely correlated with the levels of C3a and C5a. In contrast, PMMA membranes led only to slight complement activation with an associated fall in WBC counts of 29%, and PAN membranes induced very little complement activation without leukopenia. In vitro studies involving incubation of normal human plasma with each of the three membranes corroborated these findings. The results suggest that the biocompatibility of PMMA and PAN dialyzers is superior to CU.

Acrylic Resins↗
PubMed2004

[Clinical applications of recombinant complement inhibitors].

The complement system constitutes an important part of the innate immune system. Complement activation leads to the generation of C3a, C4a and C5a anaphylatoxins and the membrane attack complex. The anaphylatoxins mediate multiple reactions in the acute inflammatory response. Membrane attack complex inserts molecules into target membranes and causes cell lysis. The complement system can not discriminate between self and non-self cells and the inappropriate complement activation may lead to host cell damage. This destructive activity is tightly regulated by family of structurally and functionally related soluble and membrane-bound proteins, which act as inhibitors of complement system. The inappropriate complement activation plays an essential role in the pathogenesis of many diseases. In the therapy of these diseases specific recombinant complement inhibitors can be used. Recombinant complement inhibitors can be produced in large amounts by different eukaryotic or prokaryotic systems. The choice of the system depends on kind of the post-translational modifications of proteins.

Anaphylatoxins↗
PubMed1999

A new in vitro model to study interaction between whole blood and biomaterials. Studies of platelet and coagulation activation and the effect of aspirin.

We have developed a versatile in vitro chamber model with a double purpose: first, to be able to study mechanisms of bio-incompatibility, and, second, to test biomaterials at all levels of interactions, in whole blood. The use of biomaterials in the form of microscope slides as walls in the chamber makes it possible to analyse both the biomaterial surface with regard to protein and cell binding, as well as the molecular events taking place in the fluid. Incubation of blood in the chamber, for 60 min at 37 degrees C resulted in the rapid binding of complement and coagulation proteins and of leukocytes and platelets to polyvinylchloride (PVC) slides. The cells formed a layer which more or less covered the underlying surface. Unlike complement activation, as reflected by soluble C3a and C5b-9, the thrombin-antithrombin formation was completely nullified in cell-depleted plasma. Despite the fact that thrombin-antithrombin generation was also negligible in platelet-rich plasma, inhibition of platelet aggregation on the material surface with aspirin resulted in suppressed generation of thrombin antithrombin complexes. Taken together, the coagulation activation in the chamber was dependent on the presence of blood cells which suggests that bound/aggregated platelets initiate a sequence of events involving leukocytes that results in coagulation activation.

Anticoagulants↗
PubMed1992

Complement activation and adsorption of protein fragments by functionalized polymer surfaces in human serum.

The interactions between blood and polymer surfaces used in extracorporeal circulations result in variable activations of the immune system of complement. Measuring concentrations of C3a or C5a in supernatant blood or serum after contact with the surface has been the most usual way of assessing this activation. Most polymer surfaces bearing various chemical groups were found to adsorb C3a and sometimes C5a. After taking into account adsorption, a good correlation was found between total C3a generated and CH50 units consumed by most of the polymer samples tested. Measuring only C3a remaining in the fluid phase should not be considered sufficient to conclude that a material surface is not an activator of complement.

Adsorption↗
PubMed1982

Anaphylatoxin-mediated regulation of the immune response. I. C3a-mediated suppression of human and murine humoral immune responses.

The C3a fragment of the third component of complement was found to have immunosuppressive properties. C3a is capable of suppressing both specific and polyclonal antibody responses. In contrast, C3a had no effect on antigen- or mitogen-induced B or T cell proliferative responses. The carboxy-terminal arginine is essential for C3a to exhibit its immunosuppressive properties. The serum carboxypeptidase inhibitor 2-mercaptomethyl-5-guanodinopentanoic acid, which prevents cleavage of the terminal arginine that would produce C3ades Arg-77, allowed us to assay the effects of C3a on in vitro immune response systems where serum is required. When the terminal arginine is removed from C3a, the resulting C3ades Arg-77 molecule is nonsuppressive. Helper T lymphocytes are the target of C3a-mediated suppression of the immune response. Substitution of T cells by soluble T cell factors was found to abrogate the C3a suppressive activity.

Anaphylatoxins↗
PubMedDate not supplied

Complement activation and leucopenia on cellulosic haemodialyzers: influence of the membrane area and role of hydroxyl moieties.

We analysed the impact of the area of the dialysis membrane and of its content in hydroxyl moieties on the magnitude of haemodialysis-induced complement activation and leucopenia. First, in five patients successively treated with cellulose acetate membranes of different areas, we found that increase of the area results in an increase in complement activation determined by C3a levels before and at 15 min of dialysis. The levels of leucopenia were similarly affected, and a significant correlation was found between complement activation and leucopenia (r = 0.89, P less than 0.05). When we compared the biocompatibility characteristics of a dialyser made of saponified cellulose ester with those of two dialysers made of cellulose acetate, we found that index of complement activation (18.1 +/- 2 vs 9.9 +/- 1.1 and 11.5 +/- 1.1, P less than 0.01) as well as index of leucopenia (69 +/- 4 vs 40 +/- 2 and 37 +/- 3, P less than 0.001) were significantly higher on the saponified cellulose ester dialysers suggesting that hydroxyl groups of cellulosic membranes play an important role in the pathophysiology of dialysis-induced changes.

Biocompatible Materials↗
PubMed1992

The effects of aortic reconstruction and collagen impregnation of Dacron prostheses on the complement system.

Complement activation has been associated with numerous clinical hazards such as platelet aggregation, adult respiratory distress syndrome, and renal dysfunction. The complement system is activated by exposure of different biomaterials to blood. Recently a watertight knitted Dacron aortic prosthesis impregnated with bovine collagen has been developed. One potential disadvantage is that this bovine collagen may activate the complement system and evoke the production of inflammatory mediators. We conducted a prospective randomized trial to study the systemic effects of collagen-impregnated prostheses and of aortic surgery with implantation of Dacron prosthesis on the complement system in the perioperative period and at 3 months after operation. Forty-one patients randomly received either a collagen-impregnated (n = 20) or a nonimpregnated prosthesis (n = 21). Twelve patients who had cholecystectomy served as controls. CH50 consumption and C3a generation were determined to study overall complement activation. Furthermore, C3a/C3 fractions were calculated. Finally, C4 and factor B consumption were determined to evaluate the complement stimulation via the classic and the alternative pathways, respectively. We found significant activation of the complement system during the operation in both the collagen group (CH50 consumption: 40%, p = 0.03; C4 consumption: 74%, p < 0.0001; factor B consumption: 73%, p < 0.0001; C3a/C3 fraction increase: 173%,p = 0.04), and the nonimpregnated group (CH50 consumption: 40%, p < 0.0001; C4 consumption: 71%, p < 0.0001; factor B consumption: 76%, p < 0.0001; C3a/C3 fraction increase: 165%, p = 0.025), with no statistically significant differences between the groups of prostheses. Activation was initiated via both the classic and the alternative pathway. This indicates aortic implantation significantly activates the complement system, but that collagen-impregnated prostheses do not stimulate the complement system any more than its nonsealed substrate. Comparing results in patients with vascular disease with controls, a significantly increased complement activation was observed in the vascular group (CH50 consumption: 40%, p < 0.0001; C4 consumption: 74%, p < 0.0001; factor B consumption: 75%, p < 0.0001; C3a/C3 fraction: 169%, p = 0.002), compared with the controls (CH50 consumption: 71%; C4 consumption: 104%; factor B consumption: 94%; C3a/C3 fraction: 119%, all p = NS), with statistical significant differences between the vascular group and cholecystectomies (CH50: p = 0.005; C4: p = 0.002; factor B: p < 0.0001, and C3a/C3 fraction: NS). This observation demonstrates that aortic surgery with the implantation of a Dacron prosthesis significantly activates the complement system.

Adult↗
PubMed1993

Hemofiltration modifies complement activation after extracorporeal circulation in infants.

Complement and fibrinolytic factors were measured in 9 infants undergoing hemofiltration immediately after cardiopulmonary bypass in an attempt to reduce activation of these systems. Plasma levels of C3a, C5a, and terminal complement complexes increased during bypass by 460%, 85%, and 745%. Plasma levels were reduced after hemofiltration in 8 of the 9 infants, and C3a and C5a fractions were recovered in the ultrafiltrate. The observed activation of the fibrinolytic system seemed to be unaltered by hemofiltration. Fibrinolytic factors were not filtered. Our study shows that increased concentrations of complement factors in the plasma after bypass in infants may be reduced by hemofiltration.

Complement Activation↗
PubMed1990

Assays for plasma complement activation by x-ray contrast media.

Hemolytic complement activity and a C3a radioimmunoassay (RIA) were investigated for their ability to characterize contrast media (CM) with respect to complement activation. The CM tested were commercial formulations of diatrizoate, iodamide, iothalamate, ioxaglate, iohexol, and iopamidol. When plasma was exposed to CM, the hemolytic complement activity decreased and the C3a concentration increased. The C3a assay had a larger dynamic range and therefore more ability to discriminate among the CM. Using C3a data from pooled plasma or from individual donors' plasma, nonionic iopamidol (as Isovue 300) had lower complement-activating potential (P less than .005 and P greater than .05, respectively) than all of the ionic media based on diatrizoate, iothalamate, iodamide, and ioxaglate. The ranges of mean C3a values generated by saline, nonionic CM, and ionic CM were 48 to 60, 65 to 173, and 807 to 3272 ng C3a/50 microL, respectively. Complement activation was found to correlate with osmolality (r = 0.945, all media) and with molarity (r = 0.994, diatrizoates).

Complement Activation↗
PubMed1996

Complement peptides and mast cell triggering.

Mucosal type mast cells have been earlier shown to be unresponsive to the so called 'peptidergic' stimulus provided by cationic agents, such as anaphylatoxins, neuropeptides or polyamines. We studied the relationship between mast cells' secretory response to stimulation via their type I Fc epsilon receptors (Fc epsilonRI) and that provided by C5a and C3a fragments of the complement system, in the rat mucosal-type mast cell line RBL-2H3. Our results shown here reveal a novel function of C3a, its inhibitory capacity on IgE-mediated triggering of mucosal mast cells. This activity of C3a is most probably mediated by its interaction with the beta-chain of Fc epsilonRI. While connective tissue type mast cells are known to be activated by micromolar concentrations of the complement peptides C3a and C5a, the amount of C3a necessary for the inhibition of antigen-induced degranulation of mucosal cells in our assays is in the nanomolar range. Interestingly, the other anaphylatoxic peptide C5a, which is known to be much more effective in several biological assays, did not show any activity in the same test-system.

Animals↗
PubMed1996

Complement system response to decompression.

A role for the activated complement system in the pathogenesis of decompression sickness has recently been suggested. In this study we aimed at evaluating the response of the complement system to decompression in 24 human volunteers. A significant reduction was observed in the levels of iC3, which is a conformationally changed form of the third complement component (C3), and C3A after decompression (P < 0.001). The levels of total C3 did not change during the experiment. A relatively mild decompression has thus led to a distinct change in the complement activation profile in human volunteers.

Adult↗
PubMed1986

Different complement and granulocyte activation in patients dialyzed with PMMA dialyzers.

Plasma C3a and C5a levels as well as plasma levels of granulocyte lactoferrin, granulocyte myeloperoxidase and granulocyte elastase in complex with alpha 1-proteinase inhibitor (E-alpha 1PI) were investigated in 10 patients (52.7 +/- 5.9 years) undergoing maintenance hemodialysis (39.4 +/- 12.4 months) with hollow fiber dialyzers made from polymethylmethacrylate. Plasma levels of lactoferrin increased from 166.5 +/- 28.5 to 712.5 +/- 165.9 ng/ml, myeloperoxidase from 59.0 +/- 15.3 to 210.5 +/- 33.9 ng/ml and E-alpha 1PI from 114.2 +/- 18.1 to 681.8 +/- 102.6 ng/ml during dialysis. In contrast, plasma C3a levels rose from 179.8 +/- 33.6 to maximal 276.2 +/- 45.4 ng/ml and C5a from 55.7 +/- 8.1 to maximal 101.1 +/- 14.8 ng/ml. Our data indicate that degranulation of granulocytes occurs during dialysis despite only little complement activation and mild initial granulocytopenia.

Biocompatible Materials↗
PubMed1984

Anaphylatoxin-mediated regulation of human and murine immune responses.

C3a and C5a derived from the human complement components C3 and C5, respectively, were found to possess immunoregulatory activities. C3a was found to be capable of suppressing both antigen-specific and polyclonal antibody responses. In contrast, C3a was unable to suppress antigen- or mitogen-induced B or T cell proliferative responses. Helper T cells were found to be the target of C3a-mediated immunosuppression. Suppression occurred via the generation of suppressor T cells. In contrast to the results obtained with C3a, C5a was found to augment both antigen-specific and non-specific in vitro humoral immune responses. Moreover, C5a potentiated antigen- and alloantigen-induced T cell proliferative responses. As opposed to C3ades Arg-77, C5ades Arg retained all of the immunoregulatory activity associated with the intact molecule. Helper T cells are required for C5a-mediated potentiation of the Fc fragment-mediated polyclonal antibody response. Substitution for T cells by a soluble T cell-replacing factor rendered lymphocytes refractory to the enhancing properties of C5a.

Anaphylatoxins↗
PubMed1994

Complement activation: a new participant in the modulation of fibrin gel characteristics and the progression of atherosclerosis?

The activation of the complement system has been implicated as an important mechanism in the progression of atherosclerosis. The relationship between fibrin gel characteristics and complement activation has, however, not been investigated. Zymosan-treated plasma with 87% complement activation as measured by C3a production using radioimmunoassay was found to induce changes in biophysical characteristics of fibrin network developed in both plasma and purified fibrinogen solution. Using already established methods to measure fibre thickness (mu T), permeability (T) and compaction, it was found that these networks are made of thinner fibres with increased tensile strength arranged into a matrix which renders the networks less permeable. Such networks are resistant to streptokinase-induced lysis. Fibrin networks with thin fibres in turn induced 3.7 times higher production of C3a than unmodified networks. These observations suggest the existence of positive feedback; complement activation induces major alterations in fibrin structure which in turn can induce further activation of the complement system. The detailed mechanism underlying this interrelationship is not clear at present, but this positive feedback system may play an important role in establishing a fibrin infrastructure ultimately responsible for the progression of atherosclerosis.

Arteriosclerosis↗
PubMed1976

The primary structure of porcine C3a anaphylatoxin.

Porcine C3a was generated in whole porcine serum by inulin activation of enzymes of the alternative complement pathway. The C3a anaphylatoxin was isolated according to the procedures previously described by Hugli. The complete amino acid sequence for porcine C3a was determined utilizing automatic sequencing techniques in addition to manual subtractive Edman degradation and carboxypeptidase A, B, or Y digestion of isolated peptides. Porcine C3a is composed of a polypeptide chain containing 77 amino acid residues and has a m.w. of approximately 9,000 daltons. This C3a molecule is devoid of threonine, tryptophan, and carbohydrates. The proposed primary structure for porcine C3a is as follows: (see article) Comparisons between the amino acid sequences of human and porcine C3a reveal that the six half-cystinyl and five aromatic residue positions are conserved. Conservation of these six half-cystinyl residue positions suggest that the disulfide arrangement remains identical in both anaphylatoxin molecules. Maintenance of three interconnected disulfide linkages helps to explain a near identity between the secondary structures of human and porcine C3a as indicated by circular dichroism measurements. Particular attention was focused on the COOH-terminal region of the anaphylatoxins since an arginyl residue at position 77 is functionally essential in both human and porcine C3a. Five residue positions at the carboxy termini were conserved in both C3a molecules, and the sequence Leu-Gly-Leu-Ala-Arg probably relates directly to anaphylatoxin activity. A total of 23 residue replacements occur between human and porcine C3a which accounts for a 30% difference in primary structure. Although the C3a molecules exhibit identical biologic activity, this rather large structural difference readily explains the absence of a detectable immunologic cross-reactivity.

Amino Acid Sequence↗
PubMed2006

Ligand specificity of the anaphylatoxin C5L2 receptor and its regulation on myeloid and epithelial cell lines.

During complement activation the pro-inflammatory anaphylatoxins C3a and C5a are generated, which interact with the C3a receptor and C5a receptor (CD88), respectively. C5a and its degradation product C5a-des-Arg(74) also bind to the C5a receptor-like 2 (C5L2). C3a and C3a-des-Arg(77), also called acylation-stimulating protein, augment triglyceride synthesis and glucose uptake in adipocytes and skin fibroblasts. Based on data obtained using transfected HEK293 and RBL cells, C5L2 is additionally proposed as a functional receptor for C3a and C3a-des-Arg(77). Here we use (125)I-ligand binding assays and flow cytometry with fluorescently labeled ligands to demonstrate that neither C3a nor C3a-des-Arg(77) binds to C5L2. C5L2 expression and its regulation are investigated on various cell lines by a novel C5L2-restricted binding assay and quantitative real time PCR. Dibutyryl cAMP and interferon-gamma induce up-regulation of this receptor on myeloblastic cell lines (U937 and HL-60), whereas tumor necrosis factor-alpha (TNF-alpha) has no effect. In contrast, epithelial HeLa cells are found to constitutively express C5L2 but not the C5a receptor. In HeLa cells, interferon-gamma and TNF-alpha drastically reduce C5L2 expression. No C5a-dependent Ca(2+) signaling is observed even in these cells endogenously expressing C5L2. Taken together, C5L2 is not a receptor for C3a or C3a-des-Arg(77). Thus, this receptor is unlikely to be directly involved in lipid metabolism. Instead, the identification of stimuli modifying C5L2 expression indicates that C5L2 is a highly regulated scavenger receptor for C5a and C5a-des-Arg(74).

Anaphylatoxins↗
PubMed1990

Generation of complement-derived anaphylatoxins in normal human donor corneas.

Complement-derived anaphylatoxins (C3a, C4a, and C5a) are potent, stable mediators of acute inflammation. Because human corneas contain functional complement, the authors subjected normal human donor corneas to various forms of immunologic or chemical injury to determine if the complement system could be activated and anaphylatoxins generated. The experimental cornea of each donor pair was injected with lipopolysaccharide (LPS) or immune complexes or injured by application of acid or alkali. The remaining cornea of each donor pair served as a control. After incubation of corneas in tissue culture media for 6 hours and elution in phosphate-buffered saline for 24 hours, C3a, C4a, and C5a were measured in corneal eluates by radioimmunoassay. Compared with control corneas, C3a levels were significantly increased in corneas injected with LPS or immune complexes and in corneas injured with acid or alkali. C4a levels were significantly elevated in corneas injected with immune complexes and in corneas injured with acid or alkali but not in corneas injected with LPS. C5a levels were detectable only in corneas injured with acid or alkali. These results suggest that immunologic reactions in the human cornea may activate the classic or alternative complement pathways and generate anaphylatoxins. Additionally, chemical injuries with acid or alkali generate anaphylatoxins in the cornea. Anaphylatoxins may participate in the acute inflammatory response of the human cornea to chemical or immunologic injury.

Acids↗